Loss of Memo, a novel FGFR regulator, results in reduced lifespan

Memo is a widely expressed 33‐kDa protein required for heregulin (HRG)‐, epidermal growth factor (EGF)‐, and fibroblast growth factor (FGF)‐induced cell motility. Studies in mouse embryonic fibroblasts, wild‐type or knockout for Memo, were performed to further investigate the role of Memo downstream of FGFR. We demonstrated that Memo associates with the FGFR signalosome and is necessary for optimal activation of signaling. To uncover Memo's physiological role, Memo conditional‐knockout mice were generated. These animals showed a reduced life span, increased insulin sensitivity, small stature, graying hair, alopecia, kyphosis, loss of subcutaneous fat, and loss of spermatozoa in the epididymis. Memo‐knockout mice also have elevated serum levels of active vitamin D, 1,25‐dihydroxyvitamin D3 (1,25(OH)2D), and calcium compared to control littermates expressing Memo. In summary, the results from in vivo and in vitro models support the hypothesis that Memo is a novel regulator of FGFR signaling with a role in controlling 1,25(OH)2D production and normal calcium homeostasis.—Haenzi, B., Bonny, O., Masson, R., Lienhard, S., Dey, J. H., Kuro‐o, M., Hynes, N. E. Loss of Memo, a novel FGFR regulator, results in reduced lifespan. FASEB J. 28, 327–336 (2014). www.fasebj.org

[1]  B. Lanske,et al.  FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2–SGK1 signaling pathway , 2012, Bone.

[2]  N. Hynes,et al.  MHO1, an Evolutionarily Conserved Gene, Is Synthetic Lethal with PLC1; Mho1p Has a Role in Invasive Growth , 2012, PloS one.

[3]  K. Rosenblatt,et al.  Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  D. Prié,et al.  Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[5]  M. Kuro-o.  A potential link between phosphate and aging—Lessons from Klotho-deficient mice , 2010, Mechanisms of Ageing and Development.

[6]  K. Geering,et al.  Mouse GLUT9: evidences for a urate uniporter. , 2009, American journal of physiology. Renal physiology.

[7]  R. Bansal,et al.  Phosphorylation and lipid raft association of fibroblast growth factor receptor‐2 in oligodendrocytes , 2009, Glia.

[8]  F. Maurer,et al.  Memo is a cofilin-interacting protein that influences PLCγ1 and cofilin activities, and is essential for maintaining directionality during ErbB2-induced tumor-cell migration , 2009, Journal of Cell Science.

[9]  D. Isnardon,et al.  Memo–RhoA–mDia1 signaling controls microtubules, the actin network, and adhesion site formation in migrating cells , 2008, The Journal of cell biology.

[10]  J. Hoenderop,et al.  TRPV5: an ingeniously controlled calcium channel. , 2008, Kidney international.

[11]  B. Stieger,et al.  Isolation of renal proximal tubular brush-border membranes , 2007, Nature Protocols.

[12]  B. Lanske,et al.  Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. , 2007, Matrix biology : journal of the International Society for Matrix Biology.

[13]  Y. Nabeshima,et al.  Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice. , 2007, American journal of physiology. Renal physiology.

[14]  K. Okawa,et al.  Klotho converts canonical FGF receptor into a specific receptor for FGF23 , 2006, Nature.

[15]  K. Rosenblatt,et al.  Regulation of Fibroblast Growth Factor-23 Signaling by Klotho* , 2006, Journal of Biological Chemistry.

[16]  Shaun K Olsen,et al.  Structural basis for fibroblast growth factor receptor activation. , 2005, Cytokine & growth factor reviews.

[17]  V. P. Eswarakumar,et al.  Cellular signaling by fibroblast growth factor receptors. , 2005, Cytokine & growth factor reviews.

[18]  H. DeLuca.  Overview of general physiologic features and functions of vitamin D. , 2004, The American journal of clinical nutrition.

[19]  M. Razzaque,et al.  Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. , 2004, Matrix biology : journal of the International Society for Matrix Biology.

[20]  C. Lengner,et al.  Primary mouse embryonic fibroblasts: A model of mesenchymal cartilage formation , 2004, Journal of cellular physiology.

[21]  N. Hynes,et al.  Memo mediates ErbB2-driven cell motility , 2004, Nature Cell Biology.

[22]  Y. Takeuchi,et al.  Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. , 2004, The Journal of clinical investigation.

[23]  K. Rajewsky,et al.  Stringent doxycycline dependent control of CRE recombinase in vivo. , 2002, Nucleic acids research.

[24]  Caiying Guo,et al.  A cre recombinase transgene with mosaic, widespread tamoxifen‐inducible action , 2002, Genesis.

[25]  Tadashi Kaname,et al.  Mutation of the mouse klotho gene leads to a syndrome resembling ageing , 1997, Nature.

[26]  F. Miller,et al.  Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. , 1992, Cancer research.